Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by α- and γ-Melanocyte-Stimulating Hormones
Open accessAbstract
Melanocortin peptides and at least two subtypes of melanocortin receptors (MC3-R and MC4-R) are present in brain regions involved in cardiovascular regulation. In urethane-anesthetized rats, unilateral microinjection of alpha-melanocyte-stimulating hormone (MSH) into the medullary dorsal-vagal complex (DVC) causes dose-dependent (125-250 pmol) hypotension and bradycardia, whereas gamma-MSH is less effective. The effects of alpha-MSH are inhibited by microinjection to the same site of the novel MG4-R/MC3-R antagonist SHU9119 (2-100 pmol) but not naloxone (270 pmol), whereas the similar effects of intra-DVC injection of beta-endorphin (1 pmol) are inhibited by naloxone and not by SHU9119. Hypotensive and bradycardic responses to electrical stimulation of the arcuate nucleus also are inhibited by ipsilateral intra-DVC microinjection of SHU9119. gamma-MSH and ACTH(4-10), but not alpha-MSH, elicit dose-dependent (0.1-12.5 nmol) pressor and tachycardic effects, which are much more pronounced after intracarotid than after intravenous administration. The effects of gamma-MSH (1.25 nmol) are not inhibited by the intracarotid injection of SHU9119 (1.25-12.5 nmol) or the novel MC3-R antagonist SHU9005 (1.25-12.5 nmol). We conclude that the hypotension and bradycardia elicited by the release of alpha-MSH from arcuate neurons is mediated by neural melanocortin receptors (MC4-R/MC3-R) located in the DVC, whereas the similar effects of beta-endorphin, a peptide derived from the same precursor, are mediated by opiate receptors at the same site. In contrast, neither MC3-R nor MC4-R is involved in the centrally mediated pressor and tachycardic actions of gamma-MSH, which, likely, are mediated by an as yet unidentified receptor.
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The elevation in blood pressure by γ-MSH appears to be independent of MC3/4R activation.
“The elevation in BP by γ-MSH appears to be independent of MC3/4R activation since agouti protein or inhibitors of MC3/4R did not alter the acute BP effect of γ-MSH.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [18]
MC3R and MC4R may not play an important role in mediating the sympathetic nervous system activity and blood pressure responses of γ-MSH.
“These observations suggest that these receptors may not play an important role in mediating the SNS activity and BP responses of γ-MSH.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [18]
Microinjection of an MC4R agonist into the paraventricular nucleus increased renal sympathetic nerve activity and blood pressure.
“Previous acute experiments in anesthetized animals showed that microinjection of an MC4R agonist into the PVN increased RSNA and BP [18], and the effect of hyperinsulinemia to acutely raise lumbar SNS activity was prevented by blockade of MC4R in the PVN [37].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [18]
Blood pressure increased similarly following γ-MSH injections in wild-type as well as in MC3R and MC4R deficient mice.
“In additon, BP increased similarly following γ-MSH injections in wild-type (WT) as well as in MC3R and MC4R deficent mice [18].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [18]
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- Authors
- Li, S.-J., Varga, K., Archer, P., Hruby, V. J., Sharma, S. D., Kesterson, R. A., Cone, R. D., & Kunos, G.
- Affiliations
- Virginia Commonwealth University (US)
- University of Arizona (US)
- Oregon Health & Science University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1996-08-15
- Volume
- 16
- Issue
- 16
- Pages
- 5182-5188
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6579284
- OpenAlex
- W1605254640
- Cited by
- 152
- References
- 40
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 4
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01hd030236-05, 2r01hl049938-04a2)
- National Heart, Lung, and Blood Institute (HL49938)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK17420, R01DK017420)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-30236)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- melanocortin receptors, alpha-melanocyte-stimulating hormone, gamma-MSH, cardiovascular regulation, dorsal vagal complex, medulla oblongata, arcuate nucleus, beta-endorphin, opioid receptors, SHU9119, MC3 receptor, melanocortin-4 receptor, hypotension, bradycardia, pressor response, tachycardia, naloxone
- MeSH terms
- Animals, Blood Pressure, Cardiovascular System, Carotid Arteries, Heart Rate, Injections, Intra-Arterial, Injections, Spinal, Male, Medulla Oblongata, Melanocyte-Stimulating Hormones, Vagus Nerve, Rats, Sprague-Dawley, Receptors, Corticotropin, Receptors, Melanocortin, Rats
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